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Stem Cells 101

Why are PD researchers interested in stem cells?

The ultimate goal of stem cell research for Parkinson's disease is to generate healthy dopamine neurons that can replace the dying cells associated with PD, also known as cell replacement therapy. Although early PD-specific cell replacement studies used fetal tissue as a source of dopamine cells, stem cells could become a more viable alternative because of the limited availability of fetal tissue.

In addition to their promise as a potential therapy, stem cells could also be used to create new cell models of PD. Such models may allow researchers to screen drugs more efficiently than in currently available animal models and to study the underlying biological mechanisms associated with PD in cells taken from people living with the disease.

What are stem cells and where do they come from?

Stem cells are a renewable source of tissue that can be coaxed to become different cell types of the body. The best-known examples are the embryonic stem (ES) cells found within an early-stage embryo. These cells can generate all the major cell types of the body (they are 'pluripotent').

Stem cells have also been isolated from various other tissues, including bone marrow, muscle, heart, gut and even the brain. These 'adult' stem cells help with maintenance and repair by becoming specialized cells types of the tissue or organ where they originate. For example, special stem cells in the bone marrow give rise to all the various types of blood cells (similar blood cell-forming stem cells have also been isolated from umbilical cord blood). Because adult stem cells become more committed to a particular tissue type during development, unlike embryonic stem cells, they appear to only develop into a limited number of cell types (they are 'multipotent').

What are induced pluripotent stem cells?

Induced pluripotent stem (iPS) cells, discovered in 2007, are essentially 'man-made' stem cells and share ES cells' ability to become other cell types. IPS cells are created when scientists convert or "reprogram" a mature cell, such as a skin cell, into an embryonic-like state. These cells may have potential both for cell replacement treatment approaches in patients and as disease models that scientists could use in screening new drugs.

IPS cell technology is somewhat related to a previous method called somatic cell nuclear transfer (SCNT) or 'therapeutic cloning' (the technology that gave us Dolly the Sheep). Unlike the iPS cell approach, which converts adult cells directly into stem cells, SCNT involves transferring the genetic material of an adult cell into an unfertilized human egg cell, allowing the egg cell to form an early-stage embryo and then collecting its ES cells (which are now genetic 'clones' of the person who donated the adult cell). To date, however, this has not been successfully demonstrated with human cells and iPS cell methods may be replacing SCNT as a more viable option.

A potentially exciting use for iPS cells is the development of cell models of PD. In theory, scientists could use cells from people living with PD to create iPS cell models of the disease that have the same intrinsic cellular machinery of a PD patient. Researchers could use these cell models to evaluate genetic and environmental factors implicated in PD. For more on the future of IPS cells in Parkinson's research, read an interview with Bill Langston, MD on PD Online Research.

What scientific challenges stand in the way of creating dopamine neurons from stem cells?

The scientific challenges associated with engineering dopamine neurons (regardless of cell source) extend beyond the difficult process of coaxing a stem cell into a dopamine-producing cell. Researchers not only must demonstrate that a particular type of stem cell can become a dopamine-producing cell, they must also show the ability of that stem cell to generate sufficient quantities with the specific characteristics of the mid-brain authentic dopamine neurons that are lost in PD.

Although scientists have been able to coax ES cells, iPS cells and adult stem cells to become dopamine neurons, whether these engineered dopamine neurons are sufficiently 'authentic'— that is, whether they express everything natural ones do — is unclear and difficult to measure. To date, scientists have had the most success generating robust dopamine neurons, in both quantity and quality, using ES cells.

What other issues stand in the way of stem cell research for Parkinson's disease?

Manufacturing and regulatory issues. As with any therapy offered to patients, responsible and well-regulated manufacturing procedures must be developed and enforced to ensure that clinical-grade tissues and stem cells can be produced in sufficient quality and quantity for routine use in humans. Patients and health care providers must be assured that manufactured cells will reliably and safely meet their needs without exposing them to undue risk.

Ethical/political issues. The majority of Americans support embryonic stem cell research, especially since stem cells used in research are derived from embryos left over from in vitro fertilization procedures and would otherwise be discarded as medical waste. However, a vocal minority believes that stem cell research is wrong under any circumstances. As of March 2009, after almost eight years of restrictions, U.S. policy allows scientists to receive federal funding for meritorious research involving embryonic stem cells. Nonetheless, these philosophical issues remain part of the American public discourse, and they continue to preoccupy researchers, research funders, regulatory officials, bioethicists, patient communities and the public at large.

Can new approaches like iPS cells end the ethical/political debates over ES cells?

Work with iPS cells is still new but the technologies for producing them are moving at a rapid pace. However, whether iPS cells will prove to be a realistic therapeutic alternative to ES cells remains an unanswered question. If they can be effectively developed for either cell replacement therapy or for use as disease models in the lab, they will have fewer ethical and access issues compared to ES cells.

Since their discovery, iPS cells have been generated from individuals, including those with PD. Some studies suggest that, like ES cells, dopamine cells generated from iPS cells can improve behavioral deficits in models of PD. If ultimately used for cell replacement therapy, it is also possible that iPS cells could overcome rejection issues (similar to the bodily rejection that can arise following organ transplantation) from transplanting foreign tissue. However, iPS cells share many of the same scientific challenges of ES cells, including the engineering, transplantation, manufacturing and regulatory challenges detailed above.

Why can't researchers just use adult stem cells?

As discussed earlier, Parkinson's disease researchers have attempted to use a variety of stem cell sources to generate robust dopamine neurons, such as adult bone marrow, but have so far had the greatest success working with embryonic stem cells.

Although researchers have had some success using adult stem cells to treat a few diseases, such as leukemia, this is primarily because the particular stem cell used was naturally destined to become the type of cell implicated in the disease (i.e. bone marrow stem cells naturally give rise to blood cells and can be used to treat blood diseases). Researchers have yet to find an equivalent type of stem cell for the dopamine neurons implicated in PD.

Because the human brain contains adult stem cells, some scientists have suggested that the brain could be induced to repair itself. Unfortunately, studies do not generally support the ability of the brain to replace the dopamine neurons lost in PD, making the therapeutic promise of such an approach for PD unlikely.

What is The Michael J. Fox Foundation's view on stem cell research?

Stem cell research has the potential to significantly impact the development of disease-modifying treatments for Parkinson's disease and considerable progress has been made in creating dopamine-producing cells from stem cells. The development of new cell models of PD is a particularly promising area of stem cell research, as the current lack of progressive, predictive models of PD remains a major barrier to drug development. Cell models of PD generated from stem cells could help researchers screen drugs more efficiently than in currently available animal models and study the underlying biological mechanisms associated with PD in cells taken from people living with the disease.

However, there are still many challenges to overcome before stem cell-based cell replacement therapies for PD are a reality. Work is still needed to generate robust cells, in both quality and quantity that can also survive and function appropriately in a host brain. Although ES (and now iPS) cells hold great potential, we do not yet know which stem cell type ultimately holds the greatest promise. Thus, researchers require scientific freedom to pursue research on all types — including ES, adult and IPS cells — in order to yield results for patients.

MJFF played an early role in supporting work in stem cell research for PD, including funding the original proof of principle demonstraing that ES cells could provide a robust source of dopamine neurons. Since that time, significant other funding resources—at both the state and federal levels—have been unleashed to support the whole field, allowing MJFF to continue to target our funding in other critical areas of developing therapies for PD. Stem cells are one of many potential therapeutic targets in our portolio and we continue to monitor PD-specific stem cell developments for opportunities where the Foundation can help in advancing this research.

For more information on MJFF investments in stem cell research, please search our Searchable Database of Funded Grants.

IMPORTANT CONSIDERATION:

Unfortunately, it has yet to be demonstrated that stem cells from any source are viable treatments for people with PD. No approved or widely accepted human trials using stem cells to treat PD have been reported – in the U.S. or any other country.

The promise of stem cell therapies, coupled with the slow pace of research in this area (including the nearly eight year ban on federal funding for stem cell research that has significantly delayed progress in the U.S.) has prompted reports of 'clinics' worldwide offering stem cell therapies for a variety of diseases, including PD. The treatments are generally expensive, risky and have not been rigorously demonstrated to provide a benefit for PD patients. There are still many obstacles to overcome before the promise of stem cells as a viable therapeutic option can be realized. The Michael J. Fox Foundation urges people with PD to regard unproven treatments and clinics with a 'buyer beware' skepticism.

September 2009